Autosomal dominant familial Alzheimer's disease (FAD) has been linked to mutations in genes that encode amyloid precursor proteins (APP) and two related proteins (PS1/PS2) with 7-9 transmembrane domains. Using a recently developed expression plasmid, we propose to create mice expressing relatively high level (less than 4 times endogenous) of wild-type (wt) and mutant PS1/PS2, and to determine the neurobiological/neuropathical phenotypes of these animals. Moreover, as part of an ongoing effort to generate models of APP-linked FAD using cDNA and yeast artificial chromosome/embryonic stem cell methods, we have produced a number of mouse lines that expressing wt and human APP; the influences of wt and mutant Ps1/PS2 on the biology of APP can be examined in mice harboring both transgenes. Several lines of evidence strongly encourage us in this effort: the expression plasmid vector drives the expression of APP and PS1 in a relatively copy-dependent manner; and using these approaches, we have already generated founders harboring PS1-wt and PS1-A246E cDNA transgenes and PS1 nucleic acid probes, and antibodies have demonstrated that our transgene construct expresses wt and mutant PS1 at relatively high levels (about 5 fold over endogenous). We anticipate that mice expressing high levels of mutant PS1/PS2 will develop behavioral/brain abnormalities that share features with FAD. Moreover, through breeding paradigms, lines of APP transgenic or null mice can be used to explore the interactions of PS1/PS2 and APP in the pathogenesis of disease. We are confident that these efforts will lead to development of transgenic models of FAD, the study of which will clarify the mechanisms of disease. Moreover because we plan to make these animals widely available so that they can be used by other investigators to test novel therapies for AD.